Background. We previously reported that children with diabetes and
Helicobacter pylori infection had higher levels of glycated hemoglobin
([HbA.sub.1c]) than uninfected peers. We sought to determine whether
eradication of the infection could decrease their [HbA.sub.1c] level.

Methods. Eight children with type 1 diabetes and H pylori infection
(cases) were treated to eradicate the infection. Cases were matched
(2:1) with uninfected diabetic children (controls), and their
[HbA.sub.1c] levels were monitored.

Results. As previously described, cases started with higher
[HbA.sub.1c] values than controls. More than 2 years after treatment,
cases showed a decreasing trend and controls an increasing trend in
[HbA.sub.1c] values. At the end of the study, cases and controls had
comparable [HbA.sub.1c] values.

Conclusion. These data suggest that eradication of H pylori
infection in patients with type 1 diabetes might be associated with
better control of glycemia.

**********

DIABETES MELLITUS affects more than 15 million individuals in the
United States. (1) The importance of glycemia control has been
emphasized lately by studies showing that diabetic patients with higher
levels of [HbA.sub.1c] have significantly more long-term complications
of the disease, such as retinopathy, nephropathy, and neuropathy. (2)
Infections can lead to hyperglycemia in patients with diabetes mellitus;
the mechanisms are unknown but are thought to include the secretion of
counter-regulatory hormones due to stress, as well as the production of
cytokines. Cytokines by themselves can stimulate the secretion of
insulin counter-regulatory hormones, and they can also directly affect
carbohydrate metabolism. (3) Helicobacter pylori is one of the most
common chronic bacterial infections in the world, and infection with
this bacterium has been associated with an increased production of
cytokines such as tumor necrosis factor [alpha], interferon-[gamma], and
interleukins 1, 6, and 8. (4)

Hence, we hypothesized that H pylori infection in children with
diabetes mellitus might negatively affect their glycemia. Accordingly,
we previously reported that among our patients with type 1 diabetes,
those with concomitant H pylori infection required higher doses of
insulin (1.2 vs 0.9 IU/kg per day, respectively) and yet had higher
levels of [HbA.sub.1c] (14.9% vs 11.8%, respectively) than their
uninfected counterparts. (5) These associations remained significant
after controlling for possible confounding variables such as age,
duration of diabetes, compliance, body mass index (BMI), income, sex,
and race. To further evaluate the possible association between H pylori
infection and metabolic control of diabetes, we proceeded to treat the
infected individuals with antimicrobials to determine whether
eradication of the infection would result in a decrease in their
[HbA.sub.1c] level.

METHODS

In our previous work, (5) we identified 11 children with type 1
diabetes and asymptomatic H pylori infection, as diagnosed by serology (HM-CAP, Enteric Products Inc, Stony Brook, NY) (6) and confirmed with
the urea-breath test (UBT) (Meretek UBT, Meretek Diagnostics Inc,
Houston, Tex). (7) Of these 11 patients, 2 were lost to follow-up (one
moved out of town and the other could not be located), and 9 received
antimicrobial therapy. Treatment consisted of three medications with
doses adjusted for age (<10 years or [greater than or equal to]10
years): omeprazole (10 mg or 20 mg), clarithromycin (250 mg or 500 mg),
and metronidazole (250 mg or 500 mg) twice daily for 14 days. (8) Six
weeks after completion of treatment, all patients had a UBT. Children
with a negative UBT result (implying eradication of H pylon) were then
paired with 2 uninfected subjects from the original cohort, matching for
potential confounding variables such as age, race, BMI, duration of
diabetes, and compliance with clinical appointments. Both groups were
then seen periodically for approximately 2 years and information
concerning their insulin requirement and [HbA.sub.1c] level obtained at
each visit (approximately every 3 months).

Follow-up was done by a single investigator (R.G.) unaware of the
patients' infection status and using the routine protocol of our
endocrinology service. Measurement of [HbA.sub.1c] was done with a
capillary isoelectric focusing system, previously described, (9) with a
normal reference range of 5.7% to 8.1% (J. Hempe, PhD, oral
communication, April 2001). Consent was obtained from the parents and
assent from the participating children. The study was approved by the
Institutional Review Board of the Louisiana State University Health
Sciences Center.

Statistical analyses were done with Epi Info, version 6.0 software
(Centers for Disease Control and Prevention, Atlanta, Ga). (10)
Continuous variables were analyzed with the non-parametric Mann-Whitney
rank sum test to compare distribution values for cases and controls.
Time trends in [HbA.sub.1c] for cases and controls were estimated as the
slope obtained by least squares simple linear regression, and the slopes
were compared using the test of parallelism. (11) For baseline
comparisons, two-sided tests were used to determine differences; for
follow-up trends, one-sided tests were used to determine improvement
after eradication of the infection.

RESULTS

Of the 9 patients who received antimicrobials, one was still
infected after therapy (as evidenced by a posttreatment positive UBT).
The remaining 8 patients with documented eradication of the infection
(cases) and their 16 matched subjects (controls) constitute the study
group. For the second year, 2 cases lost to follow-up and their 4
controls were excluded from analysis, leaving 6 cases and 12 controls.

At entry into the study, the median age of the participants was 12
years (range, 6 to 18 years), and 13 (52%) were male. The Table shows
that because of matching, there was no difference between cases and
controls in age, income, compliance rate, duration of diabetes, and BMI.
During the 2-year study period the median compliance rate among cases
(0.66) and controls (0.89) remained unchanged from preenrollment values,
and the median BMI increased slightly for both cases and controls (to
21.7 and 23.7 kg/[m.sup.2], respectively).

The insulin requirements for cases and controls remained relatively
constant over the observation period. The starting median values were
1.1 IU/kg/day and 0.9 IU/kg/day for cases and controls, respectively (P
= .49), and the ending daily median values were 1.2 and 1.1 IU/kg,
respectively (P = .77). The [HbA.sub.1c] values, on the other hand, as
previously described, were higher among cases than controls at the
beginning of the study (median, 13.6% and 11.0%, respectively; P = .07).
After treatment, however, cases had a steady decrease in [HbA.sub.1c]
level (slope = -0.10), whereas controls had a slightly increasing trend
(slope = +0.03), as shown in the Figure. Comparison of the two curves
(by test of parallelism) showed that the slopes were significantly
different (P = .05). At the end of the observation period, the
[HbA.sub.1c] values were similar among cases and controls (median, 11.7%
and 11.4%, respectively; P = .69).

DISCUSSION

Our previous work suggested that the presence of H pylori infection
was associated with poor control of glycemia in children with type 1
diabetes, manifested by an elevated [HbA.sub.1c] level. (5) One possible
explanation of that finding was that patients with poorly controlled
diabetes were more prone to become infected by H pylori, a notion that
has not been well studied but that does not seem to be supported by the
work of other authors. (12,13) Alternatively, the presence of H pylori
could have caused the poor control of the glycemia. To test this
hypothesis, in the present study we investigated the effect of
antimicrobial treatment and found that control of the glycemia in our
patients improved once the infection was eradicated. This was manifested
by a progressive decrease in their [HbA.sub.1c] to levels almost
identical to those seen among control subjects who had never been
infected by H pylori. Yet, the Figure suggests that even though as a
group the cases had a significant decrease in [HbA.sub.1c] l evels,
there was marked variability in individual responses. Even though the
effect on glycemia control was modest, with an average decrease in
[HbA.sub.1c] of about 2% (ie, from 13.6% to 11.7%), this degree of
decrease in [HbA.sub.1c] appears to be associated with fewer long-term
diabetic complications. (2) The beneficial effect of treatment was
evident during the first year after eradication of H pylori and
persisted throughout the second year.

Data regarding the effect of H pylori infection on the severity of
diabetes illness is scant. Ojetti et al, (14) in 1998, reported 119
adults with insulin-dependent diabetes, 42 (35%) of whom were infected
with H pylori and described no difference between infected and
uninfected patients in the daily dosage of insulin, which was not
affected by H pylori eradication. In another report by Scaillon et al
(15) in 1999, no change in the [HbA.sub.1c] level was found in adult
diabetic patients after eradication of H pylori. The reason for the
discrepancy with our results is unclear, but it might be caused by the
study of different populations (ie, adults instead of children) or a
shorter follow-up period (ie, less than 6 months instead of 2 years).

Potential limitations need to be considered in the interpretation
of our findings. First, only 8 cases and 16 controls could be studied
from our original cohort; larger studies will be necessary to confirm
our results. Second, because of the small number of patients available,
we elected not to randomize them to treatment or no treatment, but
rather, we decided to treat all and to match them to uninfected
patients, as controls. Even though matching appeared well attained in
our study, this is artificial since no two patients are alike,
especially when considering a chronic illness, such as diabetes. Third,
the so-called "regression to the mean" phenomenon in which
values in one extreme of the distribution are more likely to move toward
than away from the mean. (16) In other words, if the differences
initially detected were caused by sampling error and they did not
represent true differences, on repeat testing subjects with poor
diabetes control will tend to perform better (not worse), making it
appear as if t he treatment did provide a beneficial effect. Randomized studies will be necessary to control for this phenomenon.

The possibility that cases might have improved as a result of
increased surveillance from being in the study does not seem likely,
since compliance did not vary before or during participation in the
study neither for cases nor for controls. Also, we could not repeat the
UBT at the end of the study to confirm the infection status of cases and
controls. However, since the annual incidence of H pylori infections
(17) and reinfections (18) in children appear to be small (about 2% for
both), it is unlikely that new infections occurred in our study group.

We believe the results of the present study, along with our
previous observations, serve as preliminary data to support the
hypothesis that eradication of H pylori infection in patients with type
1 diabetes might be associated with better control of glycemia. Further
studies will need to be conducted in a randomized clinical trial to
confirm these findings and control for possible confounding variables.
If confirmed, our findings could have important implications for better
control of the glycemia of diabetic patients infected by H pylori.

(2.) DCCT Research Group: The effect of intensive treatment of
diabetes on the development and progression of long-term complications
in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-986

* Infections can elevate blood glucose levels in patients with
diabetes. Helicobacter pylori is one of the most common chronic
bacterial infections.

* Children with type 1 diabetes and H pylori infection had higher
[HbA.sub.1c] values than uninfected counterparts. Administration of
antibiotics to eradicate H pylori infection was followed by a decrease
in the [HbA.sub.1c] value.

* These findings suggest that eradication of H pylori infection in
patients with diabetes might be associated with better control of their
glycemia.

From the Divisions of Infectious Diseases and Endocrinology,
Department of Pediatrics, Louisiana State University Medical Center and
Children's Hospital, New Orleans.